IV. Combinatorial Chemistry Parallel Library Synthesis

Total Page:16

File Type:pdf, Size:1020Kb

IV. Combinatorial Chemistry Parallel Library Synthesis IV. Combinatorial Chemistry 1. Library synthesis a) in solution, parallel synthesis b) on solid support c) split and combine, one bead one compound 2. Deconvolution and Tagging 3. Dynamic Combinatoric Chemistry Parallel Library Synthesis • 12 reactions provide 9 compounds • The library members are spatially separated, so this technique can be used for solution as well as solid phase synthesis diversification divide diversification reaction reaction Split-pool Synthesis • 6 reactions lead to 9 compounds • Each library member must be compartmentalized (each compound on its own bead) to allow pooling of the library splitdiversification pool and split diversification reaction reaction An Example of Split-Pool Synthesis O NHBoc NH 1) Pd2dba3, Cl Me 2 O O SnMe O 3X 3 2) TFA 3X Me NH2 O O O 3X Me NH2 Cl NHBoc NH2 NHBoc 1) Pd2dba3, O O O 3X O O SnMe O SnMe 3X 9X 3 3X 3 2) TFA NH2 O OCl O 3X Cl NH2 Cl NHBoc 1) Pd dba , 2 3 O O 3X 3X O SnMe3 2) TFA Cl splitdiversification pool reaction Ellman, J. et al. J. Am. Chem. Soc., 1995, 117, 3306. O NH2 NH2 NH O O O O O NH 1) O NH 2 F O 2 NH NH Me NH 2 NHFmoc O O NH2 O O O O O Me O 2) piperidine Cl Cl HO2C NH2 O CO H NH2 O O 2 HO C O NH HO2C 2 1) F O O O O NH2 NH2 NHFmoc NH2 Me NH NH O NH2 O O O 2) piperidine O O Me O O Cl Cl NH2 S O S O O O 1) NH F 2 S NH2 S NHFmoc NH O NH2 O O O O NH O NH 2 Me O 2 NH O 2) piperidine Me NH Cl O O O O split diversification Cl reaction Overview of the Entire Split-Pool Library R2 O 2 O R NHFmoc NH F NHBoc Pd dba , 2 2 3 TFA NHFmoc NH O O O O SnMe O 3 1 35 Amino Acids O R 1 Cl R1 R 20 Acid 20 cpds 20 x 35 = 700 cpds Chlorides R3 H O O N N 1) piperidine Base, R3X TFA R2 R2 2) AcOH N N O 16 Alkylating O R1 Agents R1 700 cpds 20 x 35 x 16 = 11,200 cpds Split-Pool step: Ellman, J. et al. J. Am. Chem. Soc., 1995, 117, 3306. Example of the Efficiency of the Split-pool Strategy • Optimization of 154 reactions affords 105 amplification in the number of compounds R1 R1 I O H R2 N 1 O H 2 NH R R NH2 O O N H O N N O O H 62 amines H 30 alkynes N HO O H O H N O O O O 18 iodides O R1 R2 O NH R3 OH O N 3 O R O H N 30 + 62 + 62 = 154 reactions 62 acids 18 X 30 X 62 X62 = 2.1 million compounds O O O Schreiber SL et al. JACS, 1998, 120, 8565. Structural Characterization: Direct Methods Off-bead Analysis • Cleavage, then use of analytical techniques used in TOS (e.g. LC, MS, NMR) • Requires high sensitivity and high throughput format •Example: LC-UV/ MS OH OH S O Ph HO N Ph Structural Characterization: Direct Methods On-bead Analysis I • Can be used to monitor the progress of a reaction • MAS-NMR ( Magic angle spinning NMR ) is necessary due to polymer Magic angle rotor (left), rotor spinning at the magic angle (right) MAS- NMR spectrum (600 MHz) Si O OMe O O O O O O O Structural Characterization: Direct Methods On-bead Analysis II • Example: Single-bead FT-IR microspectrometry • Can be used to monitor the progress of a reaction OO OO H O HO O O O DIC, DMAP, DMF Beads in IR cell Wavelength (cm-1) Structural Characterization: Indirect Methods Deconvolution • Screen as a mixture of compounds then re- synthesize and re-assay possible candidates in active pools Drawbacks: • Interference by unwanted properties of other compounds (e.g. cytotoxicity) • Possible synergistic interaction of multiple compounds • Sub-library synthesis is cumbersome Encoding • Encoding should provide a fast and simple way to identify the structure of all library members • Classification – Spatial encoding: position of the compound provides the information about its structure (possible only in parallel synthesis) – Graphical encoding: bar codes or other graphical tags are displayed on the solid support used in the library synthesis – Chemical encoding: every reaction used in the library synthesis is recorded on the solid support by the chemical attachment of a tag • binary coding (presence or absence of a tag) or polymer based (polypeptide, DNA) – Spectrometric encoding: using a spectrometric technique (NMR, MS, Fluorescence microscopy, NMR etc.) to read tags directly from the solid support – Electronic encoding: radio frequency memory chip attached to the solid support records and emits coded information A. C. Czarnik Current. Opp. Chem. Biol. 1997, 1, 60 Encoding in Split-pool Synthesis • Optimization of 6 reactions leads to 9 compounds • Each library member must be isolated on its own bead to allow pooling of the library How do you know what compound is on a given bead after a pool step? splitdiversification pool and split diversification reaction reaction Chemical Encoding in Split-Pool Synthesis • Every diversification reaction is followed by a tagging reaction in which a tag(s) that codes for a particular transformation is covalently attached to the solid support Decoding • Every bead has tags that provide information, once cleaved, about the chemical history of that bead • Conditions for cleavage of compound and tags have to be orthogonal compound cleavage tag cleavage small molecule Binary Chemical Coding 11 10 011101 110 111 1 Building blocks Binary 00 01 001 010 100 0 (base 2) codon Tags 2 digit codon 3 digit 1 digit 22 = 4 max 11 110 1 n binary tags code for 2n building blocks Another Example 10 011 0 11 10 011101 110 111 1 Building Blocks 00 01 001 010 100 0 Tags Halogenated Aromatics As Tags • Small amount of tag can be reliable detected (0.5-1 pmol/bead) using easily automated electron capture GC in the mixture of tags based on different retention times • Inert under most reaction conditions OMe Cl OO X n X=Cl or H N HC 2 Cl Cl O X linker variable variable region electrophore W. C. Still et al. J. Org. Chem. 1994, 59, 4723 Attachment and Cleavage of Tags • Tags are attached using rhodium carbene-insertion chemistry and can be cleaved using (NH4)Ce(NO3)6 (CAN) Cl HF O (CH2)n O X cleavable N2HC OMe Cl Cl Me MeMe X O TAG Me Si X = H or Cl * O small molecule MeMe Me Me n = 1-14 Si O * O small molecule X Rh2(O2CC(Ph)3)4 OMe Cl Cl CH2Cl2, 25 °C O (CH2)n O X Cycloheptatriene Cl TAG CAN cleavable Binary Chemical Encoding of a Peptide Library • A library of decapeptides was synthesized and screened for binding to 9E10 mAb. • 7 Amino acids were used at each position (S, I, K, L, Q, E, D) • Every amino acid was assigned a 3 digit binary codon (001=S, 010=I, 011=K, 100=L, 101=Q, 110=E, 111=D) where 1=presence of a tag and 0=absence • For each step in the library synthesis there are 3 tags designated nX (total of 18 tags for a library of 117,649 members, maximum encodable is 218 = 262,144) EQKLISEEDL known to bind 9E10 H2N-X-X-X-X-X-X-E-E-D-L-G-G-G-G- OO O HO2C n Arx O NO2 linker electrophoric tag nX general formula of tags used 110 101 011 100 010 001 identified as the best binder W.C. Still et al. PNAS 1993, 90, 10923 Dynamic Combinatoric Chemistry Virtual Dynamic Combinatoric Library Virtual Dynamic Combinatoric Library - macrocycles Virtual Dynamic Combinatoric Library – carboanhydrase inhibitors Lehn et al. 2106 Virtual Dynamic Combinatoric Library Lehn et al. 2106 Virtual Dynamic Combinatoric Library – metal grids Lehn et al, PNAS, 2003, 100, 11970 Virtual Dynamic Combinatoric Library – metal grids Lehn et al, PNAS, 2003, 100, 11970 Virtual Dynamic Combinatoric Library – neuraminidase inhibitors Eliseev et al, PNAS, 2002, 99, 3382 Virtual Dynamic Combinatoric Library – neuraminidase inhibitors Eliseev et al, PNAS, 2002, 99, 3382 Virtual Dynamic Combinatoric Library – acetylcholine esterase inhibitors Sharpless et al, PNAS, 2004, 101, 1449 Bourne, Yves et al. (2004) Proc. Natl. Acad. Sci. USA 101, 1449-1454 Pseudodynamic Dipeptide Library Protease from Streptomyces griseus Angew. Chem. Int. Ed. 2004, 43, 2432. Pseudodynamic Dipeptide Library Angew. Chem. Int. Ed. 2004, 43, 2432. Pseudodynamic Dipeptide Library CA = carbonic anhydrase Angew. Chem. Int. Ed. 2004, 43, 2432. V. Diversity Oriented Synthesis Convergent Synthesis – Target oriented synthesis (TOS) • complexity-generating Synthesis planning: rxns. retrosynthetic • fragment coupling rxns. one analysis molecule Divergent Synthesis – Diversity oriented synthesis (DOS) • complexity-generating rxns. many Synthesis planning: • multicomponent coupling different forward synthetic • diversity-generating rxns. molecules analysis Molecular Complexity TOS: Retrosynthetic Analysis of Saframycin A OMe OMe OMe HO Me O Me HO Me OMe H O H OMe H H H H OMe Me OMe Me O Me N Me N Me N Me NH N N MeO MeO H MeO H H N OH NC O CN OH CN NH FmocHN NHFmoc O O O Intramolecular 2 pictet-spengler reactions Strecker Reaction Me saframycin A OMe OMe H HO Me Me CHO OH OMe OMe H NH NH Me OMe MeO 2 N OH OHC Me H N H MeO 2 H OMe HCN OH NC N HN CHO O O FmocHN Imine formation and Strecker reaction A.
Recommended publications
  • Phytochemistry and Pharmacogenomics of Natural Products Derived from Traditional Chinese Medicine and Chinese Materia Medica with Activity Against Tumor Cells
    152 Phytochemistry and pharmacogenomics of natural products derived from traditional chinese medicine and chinese materia medica with activity against tumor cells Thomas Efferth,1 Stefan Kahl,2,3,6 Kerstin Paulus,4 Introduction 2 5 3 Michael Adams, Rolf Rauh, Herbert Boechzelt, Cancer is responsible for 12% of the world’s mortality and Xiaojiang Hao,6 Bernd Kaina,5 and Rudolf Bauer2 the second-leading cause of death in the Western world. 1 Limited chances for cure by chemotherapy are a major German Cancer Research Centre, Pharmaceutical Biology, contributing factor to this situation. Despite much progress Heidelberg, Germany; 2Institute of Pharmaceutical Sciences, University of Graz; 3Joanneum Research, Graz, Austria; 4Institute in recent years,a key problem in tumor therapy with of Pharmaceutical Biology, University of Du¨sseldorf, Du¨sseldorf, established cytostatic compounds is the development of Germany; 5Institute of Toxicology, University of Mainz, Mainz, 6 drug resistance and threatening side effects. Most estab- Germany; and State Key Laboratory of Phytochemistry and Plant lished drugs suffer from insufficient specificity toward Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China tumor cells. Hence,the identification of improved anti- tumor drugs is urgently needed. Several approaches have been delineated to search for Abstract novel antitumor compounds. Combinatorial chemistry,a The cure from cancer is still not a reality for all patients, technology conceived about 20 years ago,was envisaged as which is mainly due to the limitations of chemotherapy a promising strategy to this demand. The expected surge in (e.g., drug resistance and toxicity). Apart from the high- productivity,however,has hardly materialized (1).
    [Show full text]
  • Virtual Screening for the Discovery of Bioactive Natural Products by Judith M
    Progress in Drug Research, Vol. 65 (Frank Petersen and René Amstutz, Eds.) © 2008 Birkhäuser Ver lag, Basel (Swit zer land) Virtual screening for the discovery of bioactive natural products By Judith M. Rollinger1, Hermann Stuppner1,2 and Thierry Langer2,3 1Institute of Pharmacy/Pharmacog- nosy, Leopold-Franzens University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria 2Inte:Ligand GmbH, Software Engineering and Consulting, Clemens Maria Hofbauergasse 6, 2344 Maria Enzersdorf, Austria 3Institute of Pharmacy/Pharmaceu- tical Chemistry/Computer Aided Molecular Design Group, Leopold- Franzens University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria <[email protected]> Virtual screening for the discovery of bioactive natural products Abstract In this survey the impact of the virtual screening concept is discussed in the field of drug discovery from nature. Confronted by a steadily increasing number of secondary metabolites and a growing number of molecular targets relevant in the therapy of human disorders, the huge amount of information needs to be handled. Virtual screening filtering experiments already showed great promise for dealing with large libraries of potential bioactive molecules. It can be utilized for browsing databases for molecules fitting either an established pharma- cophore model or a three dimensional (3D) structure of a macromolecular target. However, for the discovery of natural lead candidates the application of this in silico tool has so far almost been neglected. There are several reasons for that. One concerns the scarce availability of natural product (NP) 3D databases in contrast to synthetic libraries; another reason is the problematic compatibility of NPs with modern robotized high throughput screening (HTS) technologies.
    [Show full text]
  • Combinatorial and High-Throughput Screening of Materials Libraries: Review of State of the Art Radislav Potyrailo*
    REVIEW pubs.acs.org/acscombsci Combinatorial and High-Throughput Screening of Materials Libraries: Review of State of the Art Radislav Potyrailo* Chemistry and Chemical Engineering, GE Global Research Center, Niskayuna, New York 12309, United States Krishna Rajan Department of Materials Science and Engineering and Institute for Combinatorial Discovery, Iowa State University, Ames, Iowa 50011, United States Klaus Stoewe Universit€at des Saarlandes, Technische Chemie, Campus C4.2, 66123, Saarbruecken, Germany Ichiro Takeuchi Department of Materials Science and Engineering, University of Maryland, College Park, Maryland 20742, United States Bret Chisholm Center for Nanoscale Science and Engineering and Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, North Dakota 58102, United States Hubert Lam Chemistry and Chemical Engineering, GE Global Research Center, Niskayuna, New York 12309, United States ABSTRACT: Rational materials design based on prior knowledge is attractive because it promises to avoid time-consuming synthesis and testing of numerous materials candidates. However with the increase of complexity of materials, the scientific ability for the rational materials design becomes progressively limited. As a result of this complexity, combinatorial and high-throughput (CHT) experimentation in materials science has been recognized as a new scientific approach to generate new knowledge. This review demonstrates the broad applicability of CHT experimentation technologies in discovery and optimiza- tion of new materials. We discuss general principles of CHT materials screening, followed by the detailed discussion of high-throughput materials characteriza- tion approaches, advances in data analysis/mining, and new materials develop- ments facilitated by CHT experimentation. We critically analyze results of materials development in the areas most impacted by the CHT approaches, such as catalysis, electronic and functional materials, polymer-based industrial coatings, sensing materials, and biomaterials.
    [Show full text]
  • Combinatorial Chemistry: a Guide for Librarians
    City University of New York (CUNY) CUNY Academic Works Publications and Research City College of New York 2002 Combinatorial Chemistry: A Guide for Librarians Philip Barnett CUNY City College How does access to this work benefit ou?y Let us know! More information about this work at: https://academicworks.cuny.edu/cc_pubs/266 Discover additional works at: https://academicworks.cuny.edu This work is made publicly available by the City University of New York (CUNY). Contact: [email protected] Issues in Science and Technology Librarianship Winter 2002 DOI:10.5062/F4DZ0690 URLs in this document have been updated. Links enclosed in{curly brackets} have been changed. If a replacement link was located, the new URL was added and the link is active; if a new site could not be identified, the broken link was removed. Combinatorial Chemistry: A Guide for Librarians Philip Barnett Associate Professor and Science Reference Librarian Science/Engineering Library City College of New York (CUNY) [email protected] Abstract In the 1980s a need to synthesize many chemical compounds rapidly and inexpensively spawned a new branch of chemistry known as combinatorial chemistry. While the techniques of this rapidly growing field are used primarily to find new candidate drugs, combinatorial chemistry is also finding other applications in various fields such as semiconductors, catalysts, and polymers. This guide for librarians explains the basics of combinatorial chemistry and elucidates the key information sources needed by combinatorial chemists. Introduction Most librarians who serve chemists or chemistry students are familiar with the six main disciplines of chemistry. These are: Physical chemistry applies the fundamental laws of physics, such as thermodynamics, electricity, and quantum mechanics, to explain chemical behavior.
    [Show full text]
  • Macrae/LC/Mcdowall
    1074 LCGC VOLUME 18 NUMBER 10 OCTOBER 2000 www.chromatographyonline.com Chromatography Data Systems in Drug Discovery The author discusses the roles of mass spectrometry and chromatography data systems within drug discovery analytical laboratories. He also presents ways of using laboratory information management systems to integrate the chemical data. n this article I’ll examine the use of • liquid chromatography–mass spectrome- chromatography data systems in drug try (LC–MS), which is used to determine discovery. Of particular interest is ana- compound identity based on the predic- I lyzing the results of the chemical soups tion from the anticipated compound to be produced by combinatorial chemistry labo- synthesized ratories. • nuclear magnetic resonance spectroscopy, The problem is that chromatographers which serves as a backup for compound working in combinatorial chemistry can be identification and is used mainly at the in a no-win situation: the combinatorial start of the library synthesis. chemistry increases throughput, and the I’ll concentrate on HPLC and MS analy- result is that the number of samples to be sis and on the data systems used to manage assayed also increases. How can this work the data produced. If analysts in small labo- flow be managed? What can chromatogra- ratories synthesize more than 100,000 com- phers do to reduce the waiting times? One pounds per year, they generally will need to idea, presented by Sage and co-workers (1), interpret one chromatogram and one spec- is to use parallel analysis with an eight- trum per compound. Still printing on paper? channel multiplexed electrospray interface That’s a lot of trees.
    [Show full text]
  • Combinatorial Chemistry-Parallel Synthesis 1. Introduction: the Drug Discovery Process
    Medicinal Chemistry: Combinatorial Chemistry-Parallel Synthesis Agenda 1. Introduction: The Drug Discovery Process 2. Lead Discovery and Lead Optimization-Drugability -Drug-like molecules-the rule of 5 -Drug-like vs lead-like: the rule of 3 -Privileged scaffolds -Unwanted properties: frequent hitters-aggregate forming molecules 3. Combinatorial and Parallel Synthesis in Medicinal Chemistry -Historical background-objective -Compound mixtures versus single compounds -Solid phase synthesis versus synthesis in solution 4. Combinatorial Synthesis of Biopolymers -Polypeptides -Peptoids, Oligoureas, Oligocarbamates -Oligosaccharides -Oligonucletides, Oligonucleosides winter semester 09 Daniel Obrecht, Polyphor Ltd 1 Medicinal Chemistry: Combinatorial Chemistry-Parallel Synthesis Agenda 4. Combinatorial synthesis of Biopolymers (cont.) -Combinatorial synthesis-split-mixed synthesis -Tagging strategies 5. Strategies for the Synthesis of Small Molecule Libraries -Library synthesis planning -Synthesis strategies -Classical multi-component reactions (MCR’s) -Sequential multi-component reactions (SMCR’s) -Fragment-based lead discovery -Dynamic Combinatorial Synthesis; Target-guided synthesis (TGS) -Disulfide thethering -Click chemistry -Building blocks -Parallel and/or combinatorial synthesis -Parallel work-up winter semester 09 Daniel Obrecht, Polyphor Ltd 2 Medicinal Chemistry: Combinatorial Chemistry-Parallel Synthesis Agenda 6. Applications of Parallel Synthesis and Combinatorial Chemistry in Medicinal Chemistry: Case Studies -Drug targets 7.
    [Show full text]
  • Combinatorial Chemistry: Concepts, Strategies and Applications
    Trum. Natl. A cod Sci. & Tec•h., J'hilippmt:s (200 I) 23: 215-238 COMBINATORIAL CHEMISTRY: CONCEPTS, STRATEGIES AND APPLICATIONS EVELYN B. RODRIGUEZ fnstit11le of Chemistry University ofthe Philippines Los Banos College, Laguna 4031 ABSTRACT Combinatorial chem1suy started with Mcrrilield's Nobel Pri.Ge wi11111ng 1nven11on­ the solid-phase synthesis of peptides. By mid I !J80s. solid phase techniques hove been gn:atly refined so that it wns possible to make huge numbers of peptides simultaneously in the same re:u;tion vessel. using a few steps. Later, stntegies and techniques of solution phase combinatorial synthesis have been developed as well. While solid phase synthesis makes it e11sier to conduct muhi-s1ep reactions and 10 dnvc reactions to compleuon. soluuon phnse synthesis allows a much wider range of organic reactions In its earliest form. the primary objective of combinatorial chemistry was to generate large .. librarics"of molecules en masse - instead of synthesizing compounds one by uni:. as how synthetic organic chcm1s1ry h:is been practiced for the last 100 years· and ho~ to !ind the most promising "lead" pharmaceutical compounds by high throughput screening of the libraries. Although combinatorial chemistry and combinatorial technology have been mostly applied to drug and agrochemical discovery. they can be powerful tools in the diagnostic. down- stream processing. catalysis and new m3lerials sector. INTRODUCTION Combinatorial chemistry (CC) is a set of techniques for creating simultaneously a multiplicity of compounds and then testing them for various kinds of activity. It started in the early 1980s with solid-phase peptide synthesis, although it was not called combinatorial chemistry until the earl y I 990s.
    [Show full text]
  • Combinatorial Chemistry in Ethnopharmacology
    try mis & A e p h p C l i n c r a e t WM Yuen, Mod Chem appl 2013, 1:1 i d o n o s M Modern Chemistry & Applications DOI: 10.4172/2329-6798.1000e104 ISSN: 2329-6798 Editorial Open Access Combinatorial Chemistry in Ethnopharmacology John WM Yuen* School of Nursing, The Hong Kong Polytechnic University, Yuk Choi Road, Hung Hom, Kowloon, Hong Kong Special Administrative Region, Hong Kong Biodiversity of natural products supplies an enormous source of drug Vast amount of data generated from major research contributions discovery leads. It is the general belief that the nature of natural products must be recorded and assessable by building libraries of medicinal are highly likely to provide therapeutic hits, because there are a greater chemistry. It is the truth that medicinal chemistry space is expanding number of stereocentres that intensifies scaffold diversity as supplied due to the continuous efforts in screening and testing many herbs and by the organic structures of more fused, bridged and spirocarbocyclic herbal formulations. Currently, several existing botanical databases rings [1]. The successful isolation of resveratrol from grapes has have retained chemical structure and phytochemical data of traditional remarked the benefits in promoting metabolic health by consuming red Chinese medicine, but many of these data are overlapping and in a wines, suggesting the pharmaceutical values as a potential treatment for non-standardized infrastructure format [12]. More importantly, none metabolic syndromes [2]. There are approximately 40% of all medicines of these databases contains biological information that is significant especially, 60% of anticancer agents and 80% of antimicrobials available for determining the bioactivity of chemical compounds.
    [Show full text]
  • Small and Random Peptides: an Unexplored Reservoir of Potentially Functional Primitive Organocatalysts
    Review Small and Random Peptides: An Unexplored Reservoir of Potentially Functional Primitive Organocatalysts. The Case of Seryl-Histidine Rafal Wieczorek 1, Katarzyna Adamala 2, Tecla Gasperi 3, Fabio Polticelli 3,4 and Pasquale Stano 5,* 1 Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland; [email protected] 2 Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA; [email protected] 3 Department of Science, Roma Tre University, Viale G. Marconi 446, 00146 Rome, Italy; [email protected] (T.G.); [email protected] (F.P.) 4 National Institute of Nuclear Physics, Roma Tre Section, Via della Vasca Navale 84, 00146 Rome, Italy 5 Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Campus Ecotekne (S.P. 6 Lecce-Monteroni), 73100 Lecce, Italy * Correspondence: [email protected]; Tel.: +39-0832-298709; Fax: +39-0832-298732 Academic Editor: Pier Luigi Luisi Received: 5 February 2017; Accepted: 5 April 2017; Published: 9 April 2017 Abstract: Catalysis is an essential feature of living systems biochemistry, and probably, it played a key role in primordial times, helping to produce more complex molecules from simple ones. However, enzymes, the biocatalysts par excellence, were not available in such an ancient context, and so, instead, small molecule catalysis (organocatalysis) may have occurred. The best candidates for the role of primitive organocatalysts are amino acids and short random peptides, which are believed to have been available in an early period on Earth. In this review, we discuss the occurrence of primordial organocatalysts in the form of peptides, in particular commenting on reports about seryl-histidine dipeptide, which have recently been investigated.
    [Show full text]
  • A Review on Combinatorial Chemistry
    Research & Reviews: Journal of Chemistry e-ISSN:2319-9849 p-ISSN:2322-00 A Review on Combinatorial Chemistry Shaikh SM1*, Nalawade2, Shete AS1 and Doijad RC1 1Department of Pharmaceutics and Quality Assurance, Shree Santkrupa College of Pharmacy, Ghogaon, Karad, Maharashtra, India 2Appasaheb Birnale College of Pharmacy, Sangli, Maharashtra, India Review Article Received date: 02/04/2016 ABSTRACT Accepted date: 13/04/2017 Present review article is the study on the combinatorial chemistry. Published date: 19/04/2017 This study is important when introducing drug molecule in to clinical therapy. Combinatorial chemistry means the systemic and repetitive *For Correspondence covalent connection of different molecular entities i.e., with different building blocks. We are studying the principle, design of combinatorial Shaikh SM, Department of Pharmaceutics and chemistry. We used different approaches for creating chemical libraries Quality Assurance, Shree Santkrupa College and identification of active ingredients with different types and their of Pharmacy, Ghogaon-415 111, Karad, advantages and disadvantages. Further detailed study deals with methods Maharashtra, India, Tel: 02164257404. of combinatorial chemistry in which methods are responsible for formation of new molecule with the huge application of combinatorial chemistry with E-mail: [email protected] systemic and repetitive connection by chemical bonding. We also studied the biological activity of newly synthesized molecule against their targets. Keywords: Combinatorial chemistry, QSAR, Drug discovery INTRODUCTION Drug Discovery The fields of medicine include medicinal chemistry, pharmacology, pharmaceutical biotechnology by which drug entities are discovered. Many decants drugs were discovered for identifying the active ingredient from traditional entities discovery. Recently synthesized small entities, natural formulated products or extracts were screened in intact cells or whole materials to identify substances which are desirable for therapeutic action.
    [Show full text]
  • Mass Spectrometry in High Throughput Analysis
    Spectroscopy 17 (2003) 663–680 663 IOS Press Mass spectrometry in high throughput analysis Elizabeth Want a,b, Michael Greig c,BruceComptond, Ben Bolaños c and Gary Siuzdak a,b,∗ a The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA b Mass Consortium Corporation, 3030 Bunker Hill Street, San Diego, CA 92109, USA c Pfizer Global Research and Development – La Jolla Laboratories, Agouron Pharmaceuticals, Inc., 10770 Science Center Drive, San Diego, CA 92121, USA d Waters Corporation, 34 Maple Street, Milford, MA 01757, USA 1. Overview High throughput mass spectrometry has been motivated largely from recent developments in both chemistry and biology. For instance, in chemistry, the production of large populations of molecular li- braries increases the probability that novel compounds of practical value will be found, yet also requires that their identity be confirmed and purity assessed [1–6]. While many fields of research have been in- fluenced by this approach, the largest investment has come from the pharmaceutical, biotechnology and agrochemical arena. In the field of drug development, high throughput chemistry represents a conver- gence of chemistry with biology, made possible by fundamental advances in automation, such as that of mass spectrometry [7–19]. High throughput technology has even been extended to proteomics, where mass spectrometry is being used as a tool in rapid protein identification [20–22]. Electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry have become useful for qualitative, and more recently, quantitative analysis, aiding the development of mass spectrometry as a high throughput tool in these different fields (Fig.
    [Show full text]
  • Target Profile Prediction and Practical Evaluation of a Biginelli-Type Dihydropyrimidine Compound Library
    Pharmaceuticals 2011, 4, 1236-1247; doi:10.3390/ph4091236 OPEN ACCESS Pharmaceuticals ISSN 1424-8247 www.mdpi.com/journal/pharmaceuticals Article Target Profile Prediction and Practical Evaluation of a Biginelli-Type Dihydropyrimidine Compound Library Petra Schneider, Katharina Stutz †, Ladina Kasper †, Sarah Haller, Michael Reutlinger, Felix Reisen, Tim Geppert and Gisbert Schneider * Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Str. 10, CH-8093 Zurich, Switzerland † These authors contributed equally to this work. * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +41-44-633-7438; Fax: +41-44-633-1379. Received: 26 August 2011; in revised form: 13 September 2011 / Accepted: 16 September 2011 / Published: 20 September 2011 Abstract: We present a self-organizing map (SOM) approach to predicting macromolecular targets for combinatorial compound libraries. The aim was to study the usefulness of the SOM in combination with a topological pharmacophore representation (CATS) for selecting biologically active compounds from a virtual combinatorial compound collection, taking the multi-component Biginelli dihydropyrimidine reaction as an example. We synthesized a candidate compound from this library, for which the SOM model suggested inhibitory activity against cyclin-dependent kinase 2 (CDK2) and other kinases. The prediction was confirmed in an in vitro panel assay comprising 48 human kinases. We conclude that the computational technique may be used for ligand-based in silico pharmacology studies, off-target prediction, and drug re-purposing, thereby complementing receptor-based approaches. Keywords: combinatorial chemistry; drug design; in silico pharmacology; kinase inhibitor; multi-component reaction; self-organizing map Pharmaceuticals 2011, 4 1237 1.
    [Show full text]